This invention relates to topically administrable ophthalmic and otic formulations of ciprofloxacin and dexamethasone. The formulations of the present invention are suspensions that have excellent physical stability and are characterized by their easy and ready resuspendibility. Specifically, the invention relates to stable suspension formulations of ciprofloxacin and dexamethasone that lack a nonionic tonicity agent, such as glycerol or mannitol.
Spanish Patent Application No. 2,065,846 A1 (Feb. 16, 1995) discloses topically administrable ophthalmic and otic antibiotic/steroid combination products. Examples 1-3 illustrate ophthalmic suspension formulations containing certain drug combinations with excipients including nonionic polymers and nonionic surfactants. Example 1 is a formulation of clobetasone and lomefloxacin that contains a nonionic tonicity agent (glycerin). Example 2 is a formulation of fluoromethalone and norfloxacin that contains an ionic tonicity agent (sodium chloride). Example 3 is a formulation of ciprofloxacin and dexamethasone that contains a nonionic tonicity agent (mannitol).
U.S. Pat. Nos. 5,540,930 and 5,747,061 disclose topically administrable steroid suspension formulations that contain a nonionic polymer, a nonionic surfactant and a nonionic tonicity agent. The patents are directed toward xe2x80x9cstable suspensions of water-insoluble steroid drugs of particle sizes xe2x89xa615 xcexcm, which remain in such a state so as to allow for immediate suspension, when desired, even after extended periods of settlingxe2x80x9d (see the ""061 patent""s Abstract). The patents are based on a finding that xe2x80x9c[u]nexpectedly, common tonicity agents such as aqueous solutions containing 0.9% NaCl, 0.1% EDTA, or phosphate buffer, even in concentrations as low as 1 mM, can not be employed to provide stable aqueous suspensions of corticosteroids such as [loteprednol etabonate (LE)]xe2x80x9d (""061 patent, Col. 2, lines 52-56).
The ""061 patent is aimed at formulations that solved a need for xe2x80x9caqueous suspensions of corticosteroids such as LE which can be formulated without agglomerationxe2x80x9d (Col. 2, lines 57-59). The ""061 patent""s formulations contain (A) a soft steroid such as LE present as particles preferably having a mean diameter of less than about 15 microns, (B) a nonionic polymer as a suspending agent, (C) a nonionic surfactant and (D) a nonionic tonicity agent. The ""061 patent defines a xe2x80x9csoftxe2x80x9d drug as a biologically active chemical component characterized by predictable in vivo metabolism to non-toxic derivatives after it provides its therapeutic effect. The ""061 patent teaches that xe2x80x9c[i]t is essential that these components (A)-(D) be nonionic insofar as possible since it has now been discovered that the presence of ions is the major cause of cakingxe2x80x9d (Col. 3, lines 51-53). Nonionic diols such as glycerin or mannitol xe2x80x9crather than the commonly used sodium chloridexe2x80x9d are identified as the preferred tonicity agents (see Col. 3, lines 53-56). The nonionic tonicity agent is preferably present in an amount of about 0.5 to 10% by weight.
Unless indicated otherwise, all ingredient amounts presented as a percentage are in units of weight %.
The compositions of the present invention are aqueous suspension formulations of corticosteroids (dexamethasone) that avoid agglomeration. In addition to a corticosteroid, these formulations include an antibiotic (ciprofloxacin) as a second active agent. The formulations of the present invention contain an ionic tonicity agent, but are nevertheless stable so as to be immediately and easily re-suspended when desired.
The formulations of the present invention comprise a corticosteroid and an antibiotic. The corticosteroid is dexamethasone and the antibiotic is ciprofloxacin. Dexamethasone can be present in any ophthalmically or otically acceptable form having poor water solubility such that the resulting formulation is a suspension formulation. Suitable forms of dexamethasone include dexamethasone alcohol and dexamethasone acetate. Dexamethasone alcohol is the preferred form of dexamethasone. Ciprofloxacin can be present in any ophthalmically or otically acceptable form such that the ciprofloxacin ingredient is in solution in the final formulation. A preferred form of ciprofloxacin is ciprofloxacin hydrochloride, monohydrate.
The dexamethasone ingredient will comprise about 0.01-0.5% and the ciprofloxacin ingredient will comprise about 0.1-0.4% of the formulations of the present invention. The preferred amounts of dexamethasone and ciprofloxacin in the formulations of the present invention are 0.1% and 0.3%, respectively.
In addition to the active agents, the formulations of the present invention contain sodium chloride as an ionic tonicity agent. The amount of NaCl will depend on the desired tonicity for the final formulation, but will generally range from 0.1-0.9%. For ophthalmic and otic applications, the suspension formulations of the present invention preferably contain an amount of NaCl sufficient to cause the formulations to have an osmolality of about 250-350 mOsm.
The suspension formulations also contain a nonionic polymer. Many ophthalmically and otically acceptable nonionic polymers are known. These polymers include hydroxyethyl cellulose; hydroxypropylmethyl cellulose; methyl cellulose; carboxymethyl cellulose; polyvinyl pyrrolidone and polyvinyl alcohol. The preferred nonionic polymer is hydroxyethyl cellulose. The nonionic polymer will be present in the formulations of the present invention in an amount of about 0.1-0.5%. In the case of hydroxyethyl cellulose, the preferred concentration of nonionic polymer is 0.2%.
The formulations of the present invention also contain a nonionic surfactant in an amount from about 0.01-0.2%. Many ophthalmically and otically acceptable nonionic surfactants are known. Suitable nonionic surfactants include tyloxapol; polyoxyethylene sorbitan esters, such as polysorbate 20, polysorbate 60, and polysorbate 80; polyethoxylated castor oils, such as Cremaphor EL; polyethoxylated hydrogenated castor oils, such as HCO-40; and poloxamers. The preferred surfactant is tyloxapol.
If desired, the formulations may contain a quaternary ammonium halide as a preservative. Suitable quaternary ammonium halides include polyquaternium-1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride (xe2x80x9cBACxe2x80x9d) and benzalkonium bromide. In general, the amount of the preservative ingredient will range from about 0.005-0.3%. In the preferred case where the preservative is BAC, it is preferably present at a concentration of 0.01%.
If desired, a chelating agent may also be present in the suspension formulations of the present invention. Suitable chelating agents include edetate disodium (xe2x80x9cEDTAxe2x80x9d); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate. Most preferred is EDTA. The chelating agent, if any, will typically be present in an amount from about 0.001-0.1%. In the case of EDTA, the chelating agent is preferably present at a concentration of 0.01%.
In the case of preserved or multi-dose formulations, the suspension formulations of the present invention may contain boric acid in an amount from 0.1-1.5%.
The formulations of the present invention have a pH from 3-5, preferably 4.5. pH can be adjusted with NaOH/HCl. The preferred buffering system for the formulations is a combination of sodium acetate and acetic acid. The concentration of sodium acetate will generally range from 0.015-0.06%, and will preferably be about 0.03%. The concentration of acetic acid will generally range from 0.02-0.08, and will preferably be about 0.04%.
The average particle size (mean volume basis) of the dexamethasone ingredient should be less than 10 xcexcm to avoid irritation or discomfort. The average particle size is preferably less than 6 xcexcm and most preferably less than 3 xcexcm. Dexamethasone particles can be sized using known techniques, such as ball-milling, microfluidization and sonication.
The suspension formulations of the present invention are intended for topical administration to the eye, ear or nose.
The following examples are intended to illustrate, but not limit, the present invention.